A scoping review of trials for cell-based therapies in human spinal cord injury.

INTRODUCTION: Spinal cord injury (SCI) is associated with significant and life-long disability. Yet, despite decades of research, no regenerative treatment has reached clinical practice. Cell-based therapies are one possible regenerative strategy beginning to transfer to human trials from a more extensive pre-clinical basis. METHODS: We therefore conducted a scoping review to synthesise all cell-based trials in SCI to consider the current state of the field and the cell transplant type or strategy with greatest promise. A search strategy of MEDLINE returned 1513 results. All clinical trials including adult human patients with acute or chronic, compete or incomplete SCI and a recorded ASIA score were sought. Exclusion criteria included non-traumatic SCI, paediatric patients and animal studies. A total of 43 studies, treating 1061 patients, were identified. Most trials evaluated cells from the bone marrow (22 papers, 660 patients) or the olfactory bulb (10 papers, 245 patients). RESULTS: Cell transplantation does appear to be safe, with no serious adverse effects being reported in the short-term. 86% of trials described efficacy as a primary outcome. However, varying degrees of outcome reporting prevented meta-analysis. No emerging cell type or technique was identified. The majority of trials, 53%, took place in developing countries, which may suggest more stringent regulatory requirements within Western countries. CONCLUSION: We believe cell-based transplantation translation remains in its infancy and that, although further robust clinical research is required, it is an important strategy to consider in the treatment of SCI.

Review and meta-analysis of neuropsychological findings in autoimmune limbic encephalitis with autoantibodies against LGI1, CASPR2, and GAD65 and their response to immunotherapy.

OBJECTIVES: It is assumed that autoimmune limbic encephalitis (ALE) demonstrates distinct neuropsychological manifestations with differential responses to immunotherapy according to which associated autoantibody (AAB), if any, is identified. Towards investigating whether this is the case, this study aims to summarize respective findings from the primary literature on ALE with AABs binding to cell surface neural antigens and ALE with AABs against intracellular neural antigens. METHODS: We chose ALE with AABs against leucine-rich, glioma inactivated protein 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) as the most frequent cell surface membrane antigens, and ALE with AABs to Embryonic Lethal, Abnormal Vision, Like 1 (ELAVL) proteins (anti-Hu) and glutamic acid decarboxylase 65 (GAD65) as the most frequent intracellular neural antigens. The PubMed and Scopus databases were searched on March 1st, 2021 for neuropsychological test and -screening data from patients with ALE of these AAB-types. Findings were reviewed according to AAB-type and immunotherapy status and are presented in a review section and are further statistically evaluated and presented in a meta-analysis section in this publication. RESULTS: Of the 1304 initial hits, 32 studies on ALE with AABs against LGI1, CASPR2, and GAD65 reporting cognitive screening data could be included in a review. In ALE with AABs against LGI1, CASPR2 and GAD65, memory deficits are the most frequently reported deficits. However, deficits in attention and executive functions including working memory, fluency, and psychological function have also been reported. This review shows that ALE patients with AABs against both LGI1 and CASPR2 show higher percentages of neuropsychological deficits compared to ALE patients with AABs against GAD65 before and after initiation of immunotherapy. However, the methodologies used in these studies were heterogenous, and longitudinal studies were not comparable. Moreover, 21 studies including ALE patients with AABs against LGI1 and GAD65 were also suitable for meta-analysis. No suitable study on ALE with AABs against ELAVL proteins could be identified. Meta-Analyses could be executed for cognitive screening data and only partially, due to the small number of studies. However, in statistical analysis no consistent effect of AAB or immunotherapy on performance in cognitive screening tests could be found. CONCLUSION: Currently, there is no definite evidence supporting the notion that different AAB-types of ALE exhibit distinct neuropsychological manifestations and respond differently to immunotherapy. Overall, we could not identify evidence for any effect of immunotherapy on cognition in ALE. More systematic, in-depth and longitudinal neuropsychological assessments of patients with different AAB-types of ALE are required in the future to investigate these aspects.

Multi-target approaches to CNS repair: olfactory mucosa-derived cells and heparan sulfates.

Spinal cord injury (SCI) remains one of the biggest challenges in the development of neuroregenerative therapeutics. Cell transplantation is one of numerous experimental strategies that have been identified and tested for efficacy at both preclinical and clinical levels in recent years. In this Review, we briefly discuss the state of human olfactory cell transplantation as a therapy, considering both its current clinical status and its limitations. Furthermore, we introduce a mesenchymal stromal cell derived from human olfactory tissue, which has the potential to induce multifaceted reparative effects in the environment within and surrounding the lesion. We argue that no single therapy will be sufficient to treat SCI effectively and that a combination of cell-based, rehabilitation and pharmaceutical interventions is the most promising approach to aid repair. For this reason, we also introduce a novel pharmaceutical strategy based on modifying the activity of heparan sulfate, an important regulator of a wide range of biological cell functions. The multi-target approach that is exemplified by these types of strategies will probably be necessary to optimize SCI treatment.